Yersinia pestis, the cause of the devastating disease plague, is classified as a Category A select agent due to its elevated potential for transmissibility, rapid disease progression, and high morbidity and mortality, particularly by the aerosol route. Primary pneumonic plague results when an individual inhales aerosols or droplets carrying Y. pestis, and as such is highly contagious and almost always fatal. A mouse model of infection shows that primary pneumonic plague is a surprisingly biphasic syndrome, in which the infection begins with a quiescent or anti-inflammatory state in the first 24-36 hours that subsequently transitions to a highly pro-inflammatory state by 48 hours. Thus, in order to survive, replicate, and be transmitted to new hosts, Y. pestis must be able to control and respond to a rapidly changing host environment. A necessary component of Yersinia virulence during infection is the plasmid-based YscType III secretion system (T3SS) that delivers six effector proteins directly into the cytosol of host cells. Together these proteins, termed Yops, are thought to modulate the host response to prevent phagocytosis, inflammation, and activation of effective immunity against Yersinia species, particularly early in the infection. Due to the requirement of the T3SS to plague virulence in the lung and the differential gene expression pattern of the effector Yops during infection, I predict that the relative contributions of the Yops to the pulmonary infection change as the types of host cells and inflammatory state of the lungs are altered. Therefore, the goals of this study are 1) to determine how each of the six effector Yops contribute to the virulence of Y. pestis and changing host inflammatory state during primary pneumonic plague in the mouse model of infection via the targeted deletion of these genes from a fully virulent strain, and 2) to examine how the timing of bacterial gene expression affects the ability of Y. pestis to modulate the transition between the anti- and pro-inflammatory states in the lung by altering Yop expression using an exogenously inducible promoter system. In so doing, I anticipate developing a better understanding of how Y. pestis is able to successfully infect the lungs and cause disease, which will facilitate the identification of targets for vaccine development and treatment for this public health threat.